The use of elevated HPA activity as a biomarker for depression is limited by uncertainty as to the relationship between HPA activity, mood, and antidepressant (AD) effects. Increased HPA activity in depression has been attributed to impaired glucocorticoid feedback inhibition that can be corrected by antidepressant-induced increases in brain glucocorticoid (GR) and mineralocorticoid (MR) receptors. However, benefits to some depressed patients from antiglucocorticoid therapies suggest that increasing GR or MR may not be required or appropriate for antidepressant action, and further suggest that by increasing glucocorticoids, elevated HPA activity might be a cause, as well as a marker, of depression. To discriminate the role of decreased GR from that of increased glucocorticoid levels in HPA-related depression pathology, this proposal uses forebrain GR knockout (FBGRKO) mice, a model of HPA-hyperactive depression, to test the hypothesis that that basal and antidepressant-induced changes in depression behaviors depend on changes in glucocorticoid secretion. Aim I will define the relationship of basal and stress-induced HPA activity to acute and chronic antidepressant actions to identify conditions for testing glucocorticoid and antidepressant effects. Aim II will determine glucocorticoid effects on basal behavior by testing if adrenalectomy and fixed glucocorticoid replacement normalizes depression-like behavior in FBGRKO mice. Aim III will determine the role of glucocorticoids in antidepressant action by using adrenalectomized FBGRKO and floxed GR controls with and without fixed glucocorticoid replacement to test if chronic antidepressant treatment normalizes behavior and hypothalamic- pituitary activity independently of changes in glucocorticoids. These studies address long-standing theories and contradictions of the roles of corticosteroid receptors and glucocorticoids in depression. Forebrain GR- and glucocorticoid-independent effects identified by this work could explain how antidepressants normalize elevated HPA activity in depression without facilitating adverse glucocorticoid effects on mood. This information could be used to predict and monitor antidepressant response more accurately in HPA-hyperactive depression. PUBLIC HEALTH RELEVANCE This project will determine if adrenal glucocorticoid hormones, which often increase in depression, might contribute to depression symptoms and influence antidepressant effects. This information could help to identify more effective antidepressants for depressed patients with abnormal glucocorticoid levels and to design hormone tests that detect antidepressant response more accurately. Since depression recovery depends on early effective treatment, results from this work could ultimately reduce the public health costs of depression by maximizing initial treatment success.